Effects of acarbose treatment on markers of insulin sensitivity and systemic inflammation

Background: This study assessed the effect of postprandial glucose reduction by acarbose on insulin sensitivity and biomarkers of systemic inflammation. Methods: This was a single-center, double-blind, randomized, placebo-controlled, crossover study <40 weeks in duration, involving 66 subjects with varying degrees of glucose tolerance. Eligible patients completed a 3-week run-in period and were randomized to receive either 100 mg of acarbose three times daily followed by placebo, or vice versa, lasting 12 weeks each with a 12-week washout between interventions. Liquid meal challenges and hyperinsulinemic-euglycemic glucose clamp were performed at weeks 0, 12, 24, and 36. Results: Fasting proinsulin levels and proinsulin-to-adiponectin ratios but not fasting adiponectin levels were significantly lower during acarbose versus placebo treatment. Clamp-derived insulin sensitivity index and body weight were unchanged by the intervention. Levels of fasting insulin, fasting glucose, monocyte chemoattractant protein-1, interleukin-6, and interleukin-1 beta were comparable between treatments. In the liquid meal challenge tests, postprandial glucose and insulin responses were significantly lower during acarbose versus placebo treatment. The effects of acarbose on the reduction of fasting proinsulin was most pronounced in subjects with impaired fasting glucose/impaired glucose tolerance (n = 24). Conclusions: Reduction of the glycemic load by acarbose decreased fasting levels of proinsulin but had no effect on adiponectin and whole-body insulin sensitivity as well as biomarkers reflecting inflammation. The preventive effects of acarbose on type 2 diabetes mellitus and cardiovascular risk need further investigation and cannot be explained by changes of insulin resistance and inflammatory biomarkers

Intra-individual reproducibility of galectin-1, haptoglobin, and nesfatin-1 as promising new biomarkers of immunometabolism

BACKGROUND: Galectin-1, haptoglobin, and nesfatin-1 have recently emerged as promising biomarkers implicated in immunometabolism. However, whether single blood measurements of these analytes could be suitable for large-scale human studies has not yet been evaluated. METHODS: The concentrations of galectin-1, haptoglobin, and nesfatin-1 were measured over a 4-month period in 207 healthy adults with median age of 56.7 years. Biomarker intra-individual reproducibility was assessed based on calculation of intraclass correlation coefficients (ICCs) and examining Bland-Altman plots. RESULTS: The overall ICCs were excellent for nesfatin-1 (ICC: 0.89 (95% CI: 0.86, 0.92), and good for galectin-1 and haptoglobin (ICCs: 0.70 (95% CI: 0.61, 0.77) and 0.67 (95% CI: 0.57, 0.74), respectively). Bland-Altman plots supported a high level of agreement between repeated biomarker measurements. CONCLUSIONS: Assay measurements of galectin-1, haptoglobin, and nesfatin-1 showed good to excellent within-subject reproducibility over a 4-month period, indicating that they may serve as feasible and reliable biomarkers for assessing metabolic inflammation in population research

In pursuit of novel biomarkers reflecting intestinal inflammation: temporal variability and phenotypic characterisation of serum calprotectin and lactoferrin

BACKGROUND: Calprotectin and lactoferrin are emerging biomarkers associated with intestinal inflammation. Yet, little is known about the temporal variability and phenotypic characteristics of their serum measurements in human cohorts. METHODS: We assessed the within-person variation of serum calprotectin and lactoferrin concentrations measured on two occasions over a 4-month period in 207 healthy participants. We used intraclass correlation coefficients (ICCs) as a measure of reliability. We furthermore explored cross-sectional associations of calprotectin and lactoferrin with measures of anthropometry and inflammatory biomarkers using Spearman correlations and multivariable-adjusted linear regression analyses. RESULTS: Median serum concentrations of first and second measurements of calprotectin were 1,494 ng/mL [interquartile range (IQR): 1,123–2,029)] and 1,648 ng/mL (IQR: 1,139–2,486), and of lactoferrin were 455.9 ng/mL (IQR: 304.8–620.4) and 517.6 ng/mL (IQR: 352.5–734.2), respectively. In reliability analysis we observed reasonable levels of reliability for lactoferrin and calprotectin (ICC: 0.62, 95% CI: 0.51, 0.71; 0.38, 95% CI: 0.26, 0.49, respectively). Calprotectin and lactoferrin were positively correlated with each other [Rho: 0.55 (95% CI: 0.43, 0.65)], and anthropometry measures [body mass index (BMI): calprotectin, 0.14 (0.00, 0.27); lactoferrin, 0.16 (0.00, 0.30); waist circumference (WC): calprotectin, 0.16 (0.02, 0.29); lactoferrin, 0.10 (−0.06, 0.25)] and biomarkers of inflammation [interleukin-6: calprotectin, 0.34 (0.21, 0.46); lactoferrin, 0.31 (0.16, 0.44); C-reactive protein: calprotectin, 0.41 (0.26, 0.53); lactoferrin, 0.21 (0.05, 0.36); lipocalin-2: calprotectin, 0.49 (0.38, 0.59); lactoferrin, 0.75 (0.67, 0.81)]. Lipocalin-2 explained largest variation in calprotectin (23.4%) and lactoferrin (54.6%). CONCLUSIONS: These findings suggest serum calprotectin and lactoferrin as reliable biomarkers reflecting the activity and size of an inflammatory process in the gut

Hepatic insulin clearance is closely related to metabolic syndrome components

OBJECTIVE Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate the relationship between hepatic insulin clearance (HIC) and different components of metabolic syndrome and tested the hypothesis that HIC may predict the risk of metabolic syndrome. RESEARCH DESIGN AND METHODS Individuals without diabetes from the Metabolic Syndrome Berlin Brandenburg (MeSyBePo) study (800 subjects with the baseline examination and 189 subjects from the MeSyBePo recall study) underwent an oral glucose tolerance test (OGTT) with assessment of insulin secretion (insulin secretion rate [ISR]) and insulin sensitivity. Two indices of HIC were calculated. RESULTS Both HIC indices showed lower values in subjects with metabolic syndrome (P < 0.001) at baseline. HIC indices correlate inversely with waist circumference, diastolic blood pressure, fasting glucose, triglycerides, and OGTT-derived insulin secretion index. During a mean follow-up of 5.1 ± 0.9 years, 47 individuals developed metabolic syndrome and 33 subjects progressed to impaired glucose metabolism. Both indices of HIC showed a trend of an association with increased risk of metabolic syndrome (HICC-peptide odds ratio 1.13 [95% CI 0.97–1.31], P = 0.12, and HICISR 1.38 [0.88–2.17], P = 0.16) and impaired glucose metabolism (HICC-peptide 1.12 [0.92–1.36], P = 0.26, and HICISR 1.31 [0.74–2.33] P = 0.36), although point estimates reached no statistical significance. CONCLUSIONS HIC was associated with different components of metabolic syndrome and markers of insulin secretion and insulin sensitivity. Decreased HIC may represent a novel pathophysiological mechanism of the metabolic syndrome, which may be used additionally for early identification of high-risk subjects

Insulin up-regulates natriuretic peptide clearance receptor expression in the subcutaneous fat depot in obese subjects : a missing link between CVD risk and obesity?

Context: Natriuretic peptides (NP) regulate cardiovascular homeostasis and have multiple metabolic properties. Decreased levels of NP or "natriuretic handicap" are signs of insulin resistance such as central obesity. Increased expression of NP clearance receptor (NPRC) in sc adipose tissue (SAT) was observed in insulin-resistant subjects. Objective: We hypothesized that insulin acutely regulates NP receptor expression in adipose tissue. Design and Participants: NPRA,NPRB, and NPRCmRNA expression was measured in paired samples of visceral adipose tissue (VAT) and SAT from 157 subjects (108 with type 2 diabetes). The effect of insulin on NPR gene expression in SAT was studied in euglycemic-hyperinsulinemic and hyperglycemic-hyperinsulinemic clamp experiments. Additionally, the effect of insulin and glucose on NPR expression in the culture of primary human monocytes and macrophages was tested. Results: NPRA and NPRC gene expression was higher in VAT compared with SAT(P< 0.01), but only NPRC gene expression strongly correlated with fasting insulin levels (r = 0.65, P = 0.04 × 10 -3; and r = 0.54, P = 0.002, for VAT and SAT, respectively). NPRB expression was lower in VATthan in SAT in subjects with type 2 diabetes and was lower compared with nondiabetic subjects. NPRC gene expression was up-regulated in SAT during both euglycemic- and hyperglycemic-hyperinsulinemic clamps (P = 0.038 and P = 0.048, respectively), and was increased in high glucose and insulin treatment in monocytes (70.2%; P = 0.01), but not in mature macrophages. Conclusion: Insulin increased expression of NPRCin SAT independently of circulating glucose concentrations. Thus, insulin might suppress circulating NP via up-regulation of NPRC expression in obesity, providing a novel linkbetween hyperinsulinemia and obesity. Copyright © 2012 by The Endocrine Society

A polymorphism within the connective tissue growth factor (CTGF) gene has no effect on non-invasive markers of beta-cell area and risk of type 2 diabetes

Chromosomal locus 6q23 is strongly linked to type 2 diabetes (T2DM) and related features including insulin secretion in various ethnic populations. Connective tissue growth factor (CTGF) gene is an interesting T2DM candidate gene in this chromosome region. CTGF is a key mediator of progressive pancreatic fibrosis up-regulated in type 2 diabetes. In contrast, CTGF inactivation in mice compromises islet cell proliferation during embryogenesis. The aim of our study was to investigate an impact of CTGF genetic variation on pancreatic beta-cell function and T2DM pathogenesis. We studied the effect of a common CTGF polymorphism rs9493150 on the risk of the T2DM development in three independent German cohorts. Specifically, the association between CTGF polymorphism and non-invasive markers of beta-cell area derived from oral glucose tolerance test was studied in subjects without diabetes. Neither in the Metabolic Syndrome Berlin Potsdam (MESYBEPO) study (n = 1026) (OR = 0.637, CI (0.387-1.050); p = 0.077) nor in the European Prospective Investigation into Cancer and Nutrition-Potsdam (EPIC-Potsdam) (n = 3049) cohort (RR = 0.77 CI (0.49-1.20), p = 0.249 for the recessive homozygote in general model), a significant association with increased diabetes risk was observed. The risk allele of rs9493150 had also no effect on markers of beta-cell area in the combined analysis of the MESYBEPO and Tubingen Family Study (n = 1826). In conclusion, the polymorphism rs9493150 in the 5'-untranslated region of the CTGF gene has no association with T2DM risk and surrogate markers of beta-cell area

Metabolomic linkage reveals functional interaction between glucose-dependent insulinotropic polypeptide and ghrelin in humans

Rudovich NN, Nikiforova VJ, Otto B, Pivovarova O, Gogebakan, Erban A, Mohlig M, Weickert MO, Spranger J, Tschop MH, Willmitzer L, Nauck M, Pfeiffer AF. Metabolomic linkage reveals functional interaction between glucose-dependent insulinotropic polypeptide and ghrelin in humans. Am J Physiol Endocrinol Metab 301: E608-E617, 2011. First published May 17, 2011; doi:10.1152/ajpendo.00154.2011.-The gastric peptide ghrelin promotes energy storage, appetite, and food intake. Nutrient intake strongly suppresses circulating ghrelin via molecular mechanisms possibly involving insulin and gastrointestinal hormones. On the basis of the growing evidence that glucose-dependent insulinotropic polypeptide (GIP) is involved in the control of fuel metabolism, we hypothesized that GIP and/or insulin, directly or via changes in plasma metabolites, might affect circulating ghrelin. Fourteen obese subjects were infused with GIP (2.0 pmol center dot kg(-1) center dot min(-1)) or placebo in the fasting state during either euglycemic hyperinsulinemic (EC) or hyperglycemic hyperinsulinemic clamps (HC). Apart from analysis of plasma ghrelin and insulin levels, GC-TOF/MS analysis was applied to create a hormone-metabolite network for each experiment. The GIP and insulin effects on circulating ghrelin were analyzed within the framework of those networks. In the HC, ghrelin levels decreased in the absence (19.2% vs. baseline, P = 0.028) as well as in the presence of GIP (33.8%, P = 0.018). Ghrelin levels were significantly lower during HC with GIP than with placebo, despite insulin levels not differing significantly. In the GIP network combining data on GIP-infusion, EC+GIP and IIC+GIP experiments, ghrelin was integrated into hormone-metabolite networks through a connection to a group of long-chain fatty acids. In contrast, ghrelin was excluded from the network of experiments without GIP. GIP decreased circulating ghrelin and might have affected the ghrelin system via modification of long-chain fatty acid pools. These observations were independent of insulin and offer potential mechanistic underpinnings for the involvement of GIP in systemic control of energy metabolism